Low flow rate nebulizer apparatus and method of nebulization

ABSTRACT

A nebulizer device, comprising: (a) a housing defining an interior volume therewithin, including a reservoir portion for holding medicament therein for entrainment into a carrier gas to form a delivery gas mixture comprising nebulized medicament and carrier gas; (b) a discharge port connected to the housing in flow communication with the interior volume therewithin, for discharging the delivery gas mixture from the housing; (c) a jet passage member having (i) an inlet portion for introduction of carrier gas thereinto and (ii) a nozzle portion positioned in the interior volume of the housing for discharging carrier gas in jet form in the interior volume, for entrainment of medicament from the reservoir portion of the housing in the carrier gas jet, such nozzle portion comprising a nozzle orifice accommodating carrier gas flow therethrough, wherein the nozzle orifice has an equivalent orifice diameter in the range of from about 0.005 inch to about 0.020 inch.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. patent applicationSer. No. 07/846,784 filed Mar. 4, 1992, now U.S. Pat. No. 5,186,166.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a low flow rate nebulization method anda low flow rate nebulizer apparatus used in respiratory care and, inparticular, to a continuously connected, continuous low gas flow rateliquid nebulizer useful in respiratory care to deliver liquidmedications.

2. Description of the Related Art

Crtically ill patients requiring mechanical ventilation are oftenvictims of respiratory distress syndrome, status asthamaticus andpulmonary infections. Treatment of these and other severe respiratoryconditions includes medications delivered directly to the lungs of thepatient.

Respiratory delivery of medication for these conditions is preferable tooral, intravenous and subcutaneous delivery because it is non-invasive,permits rapid action of medicament, requires a relatively small dosage,is not filtered through the liver of the patient, and produces a lowincidence of systemic side effects.

Nebulized or aerosolized solutions are the preferred method ofrespiratory delivery of medication; when fragmented into smallparticles, medicants are more efficiently deposited near sites ofmedicant activity in the lung.

Respiratory medications may be delivered to the lungs of the patient asan aerosol of a liquid or a powder. Clinical aerosols are currentlygenerated by jet or ulrasonic nebulizers, metered dose inhalers (MDI)and dry powdered inhalers.

Liquid nebulizers are well known in the art. Aerosolization of liquidmedications is preformed by putting a liquid product in a chamber(nebulizer vial) that has a pressurized flow of gas through it.Utilizing the Bernoulli principle, liquid is drawn through an aspiratortube into the path of a high velocity gas and is fractured into a mist.The mist flows out of the nebulizer by inertial forces.

There are two principal types of nebulizers for the delivery of liquidmedication to the lungs: jet nebulizers and ultrasonic nebulizers. Inconventional jet nebulizers, compressed gas from a compressor orhospital air line is passed through a narrow constriction known as ajet. This creates an area of low pressure, and liquid medication from areservoir is drawn up through a feed tube and fragmented into dropletsby the airstream. Only the smallest drops leave the nebulizer directly,while the majority impact on baffles and walls and are returned to thereservoior. Consequently, jet nebulization takes several minutes tocomplete, depending upon the initial volume.

Important disadvantages of nebulizers include low lung depositionrelated to the use of tidal breathing. A substantial portion of the doseused in a jet nebulizer is retained permanently as a dead or residualvolume on baffles and internal walls of the nebulizer chamber and cannotbe released. Generally only 2-10% of the dose placed in the nebulizerever reaches the lung. The consequences are a higher drug dosage andlonger administrative time, along with the associated cost and risk ofcontamination.

Current conventional liquid aerosol drug therapy involves administeringa finite quantity (dose) of liquid medication deposited into thenebulizer vial and administered until the vial is empty. In normalpractice, the period of delivery of each dose is measured in minutes orfractions of an hour. Depending upon the severity of the illness and theduration of activity of the medication, this process is repeatedperiodically at variable frequencies.

Such intermittent drug administration has the inherent results of (1)subjecting the patient to "peaks and "valleys" of drug dosage effects,(2) requiring respiratory therapy personnel to periodically service theneeds of the patient and nebulizer by measuring doses, disconnecting,filling and reconnecting the nebulizer and periodically monitoring theadministration, and (3) disconnecting the patient from an attachedventilator during nebulizer service. Further, medication which isadministered as a large volume, such as a surfactant, now requires largemedicant flow volume through the nebulizer requiring frequent servicingand refilling of the nebulizer vial which interferes with ventilatorfunction.

In some cases, a significant proportion of the respiratory flow to thepatient is through the nebulizer such as in the operational use of theVISAN nebulizer of Burroughs Wellcome Company. In the delivery of themedicant EXOSURF® surfactant, up to half of the tidal volume flowsthrough the nebulizing ports of the nebulizer to unite with the balanceof the respiratory gas delivered directly from the ventilator in aY-shaped junction in the flow path to the patient downstream from thenebulizer. In such delivery, the nebulizing gas is synchronized with thenebulizer such that nebulizing gas is delivered to the nebulizer onlyduring the ventilatory inhalation cycle.

A nebulizer comprising a vial-like nebulizing chamber which comprises atwo-position flow control valve assembly for accessibly draining andrefilling the nebulizing chamber is disclosed in U.S. Pat. No.4,805,609. While the valve assembly provides access for resupplying amedication close while the nebulizing chamber remains in sealed relationwith the nebulizer, such resupply is service intensive and limited tovolumes containable by the nebulizing chamber.

Recent developments in respiration therapy involve aersolization anddelivery of nebulized mist on a continuous basis over several hours. Forexample, an entire day's medication dosage is delivered at a constantrate over twenty-four hours, as opposed to conventionally delivering thesame dosage as four separate aliquots at six hour intervals. Suchdelivery eliminates the "peak" and "valleys" effects of the drug,reduces respiratory personnel suport times, and also reduces the numberof time critical medication/nebulizer interconnections are interrupted,thereby diminishing the potentially dangerous exposures of the patientto the effects of respiratory circuit contamination.

Delivery of medicated mist is both in combination with a ventilator andthrough masks, mouthpieces, and other voluntary mist inhalationapparatus.

The second type of aerosol generator is a metered dose inhalator (MDI),which delivers a bolus of more concentrated drug aerosols than thesolution commonly available for nebulizers. For optimal effect, MDIdelivery systems require proper administration technique, which includescoordinated actuation of aerosol delivery with inhalation, a slowinhalation of 0.5-0.75 liters per second, a deep breath approachinginspiratory capacity inhalation, and at least 4 seconds of breathholding.

Many patients find it difficult to properly administer medication withan MDI, especially during acute exorbation. An article which appeared inEur. J. Respit. Dis., 68(5), 332 (1986), entitled "BronchodilatorEffects of a Fenoterol Meter Dose Inhaler and Fenoterol Powder inAsthmatics with Poor Inhaler Technique," described test findings showingthat the effectiveness of bronchodilator medication, when delivered withan MDI, is dependent on good MDI technique. The article suggested thatdelivery of medication in a powdered form is more reliable for patientswho do not exercise proper MDI technique.

MDIs can be equipped with devices that automatically couple actuation toinspiratory effort, thus eliminating the need for coordinating handaction with inhalation. Devices such as spacers and holding chambersalso decrease partial velocity and reduce the number of large particles.Both of these features reduce oral pharyngeal and large airwaydeposition with a consequent reduction in systemic absorption.Deposition of aerosols from an MDI with a spacer or holding chamber issimilar and perhaps better than the deposition of a properly used MDIalone.

Advantages of the MDI include deposition of 10-15% of the metered dosewith consequent short treatment time, low cost and increasedconvenience. However, MDIs cannot be used by patients requiringmechanical ventilation. Other disadvantages include the need for patientcooperation, the practical limitations and inconveniences associatedwith increased dosing requirements due to the typically small dosagesadministered with an MDI, the limited number of currently availabledrugs, and the dependence on fluorocarbons of aerosol generation.

Others have recognized the need for new inhalation devices such asmodified dry powder inhalers to replace use of MDIs due to environmentalconcerns related to the use of fluorocarbons. See "Today's Treatment ofAirway Obstruction . . . and Tomorrow's?" Flenley, D. C., Respiration,55 Suppl. 2, 4 (1989).

The third type of aerosol generator is a dry powder inhaler. Drypowdered inhalation devices currently in use are the Spinbaler, theRotahaler, the Turbohaler and the disc inhaler. Dry powdered inhalersare breath actuated and usually require a higher inspiratory flow ratethan that required for an MDI or a nebulizer. Flow rates of 1-2 litersper second are usually considered optimal, although flow rates as low as0.5 liters per second may be effective for some dry powdered inhalers.

Advantages of dry powdered inhalers include relative ease ofadministration and the fact that they do not require fluorocarbonpropellants. When a dry powdered inhaler is used properly, depositionappears to be similar to that of a properly used MDI.

However, powdered inhalers are limited by the dose they can provide andby the number of drugs currently available. Only terbutaline,salbutamol, dexamethasone and chromolyn sodium are available in powderform.

All conventional powder inhaler delivery systems utilize single dosecapsules except the Turbohaler for administration of terbutaline. Whileseveral devices have been developed which permit preloading of severalsingle dose capsules, neither these devices nor the Turbohaler haveeliminated the other disadvantages of conventional powdered inhalers.See "A New Inhalation System for Bronchodilation. Study of theAcceptance of the Ingelheim M Inhaler in Chronic Obstructive RespiratoryTract Disease." Mutterlein, B. Schmidt, B., Fleisher, W., and Freund,D., Fortschr. Med., April 15, 108(11), 225 (1990); "In Vivo Evaluationof the New Multiple Dose Powder Inhaler and the Rotahaler Using theGamma Scintigraphy," Vidaren, M., Paronen, P., Vidaren, P. Vainir, P.,and Nuutinen, J., Acta. Pharm. Nord., 2(1), 3 (1990); "Clinical Use ofDry Powder Systems," Crompton, G. K., Eur. J. Respir. Dis. Suppl., 122,96 (1962).

Other disadvantages of dry powdered inhalers include the following: a)they are usually not particle size-selective and thus heavy oralpharyngeal deposition may occur; b) high humidity environments may causeclumping of the particles; and c) dry powdered inhalers cannot be usedin ventilatory circuits.

Currently available devices for delivery of powdered medications torespiratory therapy do not employ nebulization technology.

The use of compressed air powered jet mills as a power generator forinhalation experiments is disclosed in "Use of a Jet Mill for DispersingDry Powder for Inhalation Studies," Cheng, Y. S., Marshall, T. C.,Henderson, R. R., and Newton, G. J., Am. Ind. Hya. Assoc. J., 46(8), 449(1985). The jet mill consisted of an elongated channel), one materialdelivery jet, and two high speed air jets. Powder fed into the channelwas dispersed by turbulence and centrifugal forces. The powder used inthe inhalation experiments consisted of dye materials to be tested fortoxicity. A flow rate of 400 liters per minute was maintained. Thearticle does not address nebulization of powdered medication forpurposes of respiratory therapy.

U.S. Pat. No. 4,232,002 discloses procedures for administeringantihistamines. Methods disclosed include inhalation by a patient ofmist, nebulized spray, or a cloud of fine solid particles. Products fordelivery of medication include pressurized canistor inhalers, portabledry powder insuffilators using capsules, and nebulizers. The only drypowder delivery system described is a dry powder inhaler using capsulesof dry powder in single dose units. The delivery method describedinvolves puncturing a capsule of dry powder medication which isdispersed by means of a turbomixer to be inhaled thorugh a mouth piece.This patent does not address continuous flow or continuous delivery ofinhalable medication. It does not enablingly teach or address jetnebulization of powdered solid medications, and does not teach anebulizer vial which connects to a nebulizer to provide a device forintroducing continuous flow.

U.S. Pat. No. 3,669,113 discloses a method and device for dispensingpowdered medication from a perforated container by rotating thecontainer by pneumatic means and causing the axis of rotation of thecontainer to precess and describe a path of precession which iscontained within a generally conical surface of a precession. Themechanisms described are based on varying shaft and bearingconfigurations. The method of this patent is said to be especially wellsuited to delivery of particles less than 80 microns in diameter. Thepatent does not address jet nebulization, continuous flow or continuousnebulization.

Recent developments in respiration therapy involve aerosolization anddelivery of nebulized liquids on a continuous basis over several hours.Such delivery stabilizes the effects of the medication over time,reduces respiratory personnel support time, and reduces the chances ofrespiratory circuit contamination.

In our prior co-pending U.S. patent application Ser. No. 07/729,518,filed Jul. 12, 1991, a liquid nebulizer system is disclosed comprising anebulizer attachable nebulizer vial, a large supply vessel, and a fluiddelivery system, to be used with a conventional liquid nebulizer. Theliquid nebulizer system provides for continuous delivery of liquidmedication from a large supply vessel into the nebulizer vial which isattached to a conventional nebulizing apparatus, permitting continuousdelivery of nebulized liquid medication. The disclosure of such priorcopending application is hereby incorporated herein by reference.

In conventional, commercially available liquid nebulizer systems, acarrier gas flow rate in the range of from about 6 to about 8 liters perminute is used. Such flow rate range is necessary for conventionalnebulizer devices to operate with suitable efficiency, but suchrelatively large flow rates also lead to substantial loss and wasteageof the nebulized drug, due primarily to the fact that the flow rates insuch range exceed the patient uptake rate on a continuous basis.

It is possible to reduce carrier gas flow rate below such 6-8 liter perminute range, but at such lower flow rates, nebulization efficiencybecomes disproportionately poorer as the flow rate is reduced to levelsas low as 4-5 liters per minute, with the result that a carrier gas flowrate of 4 liters per minute is considered a conventional "low flow"regime defining the limits of operability of commercially availableliquid nebulizer devices.

Further, even at such "low flow" conditions on the order of 4-5 litersper minute, the tidal volume respiratory gas is substantially largerthan lung capacity for neonatal patients and others with reduced lungcapacity such as patients who possess only one lung. At low flow rates,on the order of 4-5 liters per minute, the nebulization efficiencybecomes unsuitable since the gas flow rate is not adequate to produce ausefully fine particle size distribution of the medicant.

Accordingly, where low flow delivery of medicant materials is required,the only practical device is an ultrasonic nozzle. However, ultrasonicnozzles suffer the deficiencies that they are costly, tend to denature avariety of otherwise useful drugs which in denatured form arenon-efficacious, and ultrasonic nozzles tend to have a short operatinglife, due to nozzle wear and degradation.

It would therefore be highly desirable to provide a liquid nebulizerdevice which is usefully employed to deliver medicant materials in acarrier gas flow stream at a flow rate substantially below the range of4-5 liters per minute, which is the practical lower limit withconventional nebulizer apparatus.

Accordingly, it is an object of the present invention to provide such aliquid nebulizer system capable of operating at carrier gas flow ratessubstantially below the 4-5 liter per minute practical lower limit ofcurrently available commercial nebulizer devices.

It is another object of the present invention to provide a nebulizationsystem of such type which may be used for delivery of liquid as well assolid medicaments.

It is a further object of the present invention to provide a method andapparatus for continuous respiratory delivery by low flow rate gasnebulization of liquid medicaments.

It is still another object of the present invention to provide a methodand apparatus for respiratory delivery of low gas flow nebulization ofliquid medication which may be used in ventilatory circuits.

It is yet another object of the invention to provide a method andapparatus which overcome the disadvantages associated with currentlyavailable respiratory medicant delivery systems.

These and other objects and advantages of the present invention will bemore fuly apparent from the ensuing disclosure and appended claims.

SUMMARY OF THE INVENTION

In a broad apparatus aspect, the present invention relates to anebulizer device, comprising:

(a) a housing defining an interior volume therewithin, including areservoir portion for holding medicament therein for entrainment into acarrier gas to form a delivery gas mixture comprising nebulizedmedicament and carrier gas;

(b) a discharge port connected to the housing in flow communication withthe interior volume therewithin, for discharging the delivery gasmixture from the housing;

(c) a jet passage member having (i) an inlet portion for introduction ofcarrier gas thereinto and (ii) a nozzle portion postioned in theinterior volume of the housing for discharging carrier gas in jet formin the interior volume, for entrainment of medicament from the reservoirportion of the housing in the carrier gas jet, said nozzle portioncomprising a nozzle orifice accomodating carrier gas flow therethrough,wherein the nozzle orifice has an equivalent orifice diameter in therange of from about 0.005 inch to about 0.020 inch.

In the above-described apparatus, the nozzle orifice preferably is inthe range of from about 0.007 inch to about 0.018 inch, more preferablyfrom about 0.008 inch to about 0.015 inch, and most preferably fromabout 0.010 inch to about 0.012 inch.

The nebulizer device in one embodiment particularly suited fornebulization of liquid medicants may further comprise means disposed inthe interior volume of the housing for delivering liquid from thereservoir portion of the housing to a discharge locus of the nozzleorifice of the jet passage member, whereby delivered liquid is entrainedin carrier gas flowed through the jet passage member when the reservoirportion contains liquid. In a specific embodiment, such means maycomprise a nebulization structure mounted in the interior volume of thehousing, including: an expansion chamber in flow-receiving communicationwith the nozzle portion of the jet passage member, such expansionchamber having an orifice therein, in alignment with the orifice of thejet passage member; an impingement baffle presenting an impingementsurface in alignment with the orifices of the jet passage member and theexpansion chamber; and means for aspiratingly delivering liquid from thereservoir portion of the housing when liquid is contained in thereservoir and carrier gas is flowed in sequence through the orifices ofthe jet passage member and the expansion chamber at sufficientvolumetric flow rate. In such embodiment, the orifice in the expansionchamber has an equivalent orifice diameter in the range of from about0.025 inch to about 0.060 inch, and preferably from about 0.030 inch toabout 0.050 inch.

The nebulizer devide of the invention may further comprise pressurizedcarrier gas supply means coupled in gas-supplying relationship with theinlet portion of the jet passage member, and/or a breathing circuitcoupled with the discharge port for receiving delivery gas mixture andconveying same to a patient interconnected with the breathing circuit.

In one method aspect, the present invention relates to a method ofdelivering a nebulized medicant to a patient, comprising:

(a) providing a nebulizer apparatus including a breathing circuitcoupled to the patient and including a nebulizer device (i) containingthe medicant, and (ii) constructed and arranged for producing apulmonarily effective nebulized medicant in a carrier gas passed throughthe nebulizer device at a carrier gas flow rate in the range of fromabout 0.5 to about 3.25 liters per minute;

(b) flowing the carrier gas through the nebulizer device at a flow ratein the range of from about 0.5 to about 3.25 liters per minute, todisperse the medicant into the carrier gas and form said pulmonarilyeffective nebulized medicant in the carrier gas, as a medicant/carriergas mixture; and

(c) passing the medicant/carrier gas mixture through the breathingcircuit to a pulmonary situs of the patient.

In another method aspect, the present invention relates to a method ofdelivering a nebulized medicant to a patient, comprising:

(I) providing a nebulizer apparatus including a breathing circuitcoupled to the patient and including a nebulizer device, wherein thenebulizer device comprises:

(a) a housing defining an interior volume therewithin, including areservoir portion for holding medicament therein for entrainment into acarrier gas to form a delivery gas mixture comprising nebulizedmedicament and carrier gas;

(b) a discharge port connected to the housing in flow communication withthe interior volume therewithin, for discharging the delivery gasmixture from the housing;

(c) a jet passage member having (i) an inlet portion for introduction ofcarrier gas thereinto and (ii) a nozzle portion postioned in theinterior volume of the housing for discharging carrier gas in jet formin the interior volume, for entrainment of medicament from the reservoirportion of the housing in the carrier gas jet, such nozzle portioncomprising a nozzle orifice accomodating carrier gas flow therethrough,wherein the nozzle orifice has an equivalent orifice diameter in therange of from about 0.005 inch to about 0.020 inch;

(II) disposing a medicant in the reservoir portion of the housing;

(III) flowing the carrier gas through the jet passage member of thenebulizer device at a flow rate in the range of from about 0.5 to about3.25 liters per minute, to disperse the medicant into the carrier gasand form a pulmonarily effective nebulized medicant in the carrier gas,as a medicant/carrier gas mixture; and

(IV) passing the medicant/carrier gas mixture through the breathingcircuit to a pulmonary situs of the patient.

In the practice of the method of the present invention, the carrier gasflow rate preferably is in the range of from about 1.0 to about 3.0liters per minute, and most preferably is in the range of from about 2.2to about 2.8 liters per minute.

The medicant which is administered to the patient in the practice of thenebulization technology of the present invention may for examplecomprise a material selected from the group consisting of lungsurfactants or precursors thereof, terbutaline, salbutamol,dexamethasone, chromolyn sodium, pentamidine, and bioactive substancesencapsulated in a pulmonarily degradeable encapsulant medium.

As used herein, the term "equivalent orifice diameter" refers to thediameter of an orifice having a circular opening which is equivalent incross-sectional open area (i.e., the open area of the orifice openingperpendicular to the direction of the flow of carrier gas therethrough)to the cross-sectional open area of the actual orifice in thenebulization system of the present invention. This terminology definesthe dimensional character of the orifice regardless of the actual shapeof the orifice opening, and thus the invention contemplates theemployment of orifice openings which are of circular or generallycircular opening shape, as well as orifice openings which are ofnon-circular or irregular opening shape. Of course, when the orificeopening is of circular shape, the equivalent orifice diameter of suchopening is identical to its actual diameter. Preferably, the orificeopening is of circular shape, or at least generally circular shape,although as mentioned, other non-circular shapes, e.g., square, ovoid,rectangular, star-shape, cruciform, etc. shapes, may advantageously beemployed within the broad practice of the present invention.

As used herein, the terms "medicant" and "medicament" are intended to bebroadly construed to include any substances, formulations, compositions,compounds, materials, etc. which are physiologically beneficial.

As used herein, the term "pulmonarily effective" means physiologicallybeneficial in application to a patient at a pulmonary situs, viz., thelungs and associated inspiratory and expiratory passages and bodystructures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of a patient receiving respiratorysupport and medication via a continuous flow liquid nebulizing deviceinterposed between an endotracheal tube and a ventilator.

FIG. 2 is an exploded perspective view of a nebulizer and a continuousflow supporting system comprising a large medication storage vessel, arate controllable pump, an influent port accessible nebulizer vialseparated from the nebulizer device upper portion, and influent flowregulating and supply devices.

FIG. 3 is an elevational cross-section of the nebulizer device of FIG.2.

FIG. 4 is an elevational cross-section of a low flow rate jet structureof a type such as may be alternatively employed in the nebulizer deviceof FIG. 2.

FIG. 5 is a schematic representation of a patient receiving respiratorysupport and medication via a powder nebulizing device interposed betweenan endotracheal tube and a ventilator.

FIG. 6 is an elevational cross-section of the powder nebulizer device ofFIG. 5.

DETAILED DESCRIPTION OF THE INVENTION, AND PREFERRED EMBODIMENTS THEREOF

In this description, the term "proximal" is used to indicate the segmentof the device normally closest to the patient when it is being used. Theterm "distal" refers to the other end. Herein the term "nebulizerdevice" is defined to be a nebulizing unit or instrument used toaerosolize fluid or disperse particulate solid material, e.g., powder,for delivery to a patient. The term "nebulizer vial" is sometimes usedherein to denote the portion of a nebulizing device which comprises acontainer providing a reservoir for fluid or particulate solid materialto be nebulized. The term "nebulizer" is sometimes used herein to denotethe non-nebulizer-vial portion of the nebulizing device which comprisesat least a portion of the nebulizing mechanism. Reference is now made tothe embodiments illustrated in FIGS. 1-3 wherein like numerals are usedto designate like parts throughout.

As seen in FIG. 1, a patient 30, undergoing respiratory therapy, isfitted with an endotracheal tube 24. The proximal trunk end 18 of a"Y"-shaped connector 32 is insertably connected to a distal end 25 ofendotracheal tube 24. One bifurcated distal end 34 of "Y"-shapedconnector 32, is insertably connected to a proximal port 22 of anebulizer 20 which is part of a nebulizing device 48. Nebulizer 20 isdisposed between distal end 34 of "Y"-shaped connector 32 and a proximalend 14 of a respiratory gas delivery tube 12. Thereat a distal part 38of nebulizer 20 is insertably connected to gas delivery tube 12. Gasdelivery tube 12 provides the distal portion of inhalation respiratorypathway 26 and connects to the output inhalation gas of a ventilator 10.Ventilator 10 therapy supplies periodic, breath-sustaining pulses ofpressurized gas through tube 12, nebulizer device 48, and "Y"-shapedconnector 32 into endotracheal tube 24 and to patient 30.

The other distal end 36 of "Y"-shaped connector 32 comprises a proximalportion of an exhalation respiratory pathway 28 which further comprisestube 16 which returns exhalation flow to ventilator 10. Many differentventilators are known and available in the art. Generally, ventilatorswhich are conventionally used with nebulizers may be used with theinvention.

Nebulizer 20 receives a supply of nebulizing gas from a flow meter 40along a fluid pathway 26' which passes through a tube 42 interposed andconnected between flow meter 40 and a top nebulizer inflow connectingtube 44'. Flow meter 40 receives a pressurized gas from a gas source 44through a connecting tube 42'. Gas pressure from gas source 44 issufficient to provide the volumetric flow for which flow meter 40 ispreset. Gas source 44 may comprise pressurized oxygen or otherbreathable gas from a hospital pressurized O₂ delivery system, from atank of compressed oxygen, a blender, directly from ventilator 10, orfrom other sources of pressurized gases conventionally used inrespiratory therapy. Flow meters are well known and widely used in theart. Such flow meters may comprise macro and vernier adjustable controlsfor very accurate and precise gas flow settings. Although O₂ ispreferred for some selected medicants, source 44 may supply oxygenblended with other gases.

Nebulizing device 48 comprises nebulizer 20 which functions incombination with an attached nebulizer vial 50. Nebulizing device 48nebulizes or aerosolizes fluids contained in reservoir 72 in nebulizervial 50, thereby producing a mist which is carried to patient 30 byinfluent flow of gas from ventilator 10 through pathway 26 and bynebulizing gas received from gas source 44. Delivery of nebulized fluidto patient 30 is therefore dependent upon the availability of fluidresident in the reservoir 72 at any given moment.

In a currently preferred embodiment shown in FIGS. 1 and 2, a continuousflow system 106 provides substantially continuous delivery of fluid tonebulizer vial 50 to maintain the volume of liquid at an adequate andessentially unchanging level in reservoir 72. Continuous flow system 106comprises (i) nebulizer vial 50, (ii) at least one influent access port52 to nebulizer vial 50, (iii) connecting tubing 54 interposed between apump 60 and connected at influent access port 52, (iv) the pump 60, (v)additional tubing 58 providing a medicant pathway 56' interposed betweenand connected pump 60 and a large medicant supply vessel 70, and (vi)the large medicant supply vessel 70. Continuous flow system 106maintains a constant volume of liquid in nebulizer vial 50, in whichcontinuation of such constant volume condition is not dependent upon theinitial contents of reservoir 72 at the time nebulizer vial 50 is joinedto nebulizer 20, but upon the larger volume available in large medicantsupply vessel 70. Such supply vessels may be IV bags, bottles or othernebulizing medication and reagent containing vessels from whichtherapeutic liquids are drawn.

As seen in FIG. 2, nebulizing device 48 comprises nebulizer vial 50which releasibly and sealably attaches to nebulizer 20. Such attachmentmay be by a male threaded member 62 of nebulizer vial 50 insertablyjoined into a female threaded member 64 of nebulizer 20. When nebulizer20 is so disposed and connected to nebulizer vial 50, an end 68 of anaspirator tube 66 is disposed below the surface of a reservoir 72 in thebottom of nebulizer vial 50 as best seen in FIG. 3.

Nebulizer 20 may be a general construction similar to commerciallyavailable nebulizer devices generally used for administration ofaerosolized fluids but featuring a jet passage member having (i) aninlet portion for introduction of carrier gas thereinto and (ii) anozzle portion positioned in the interior volume of the nebulizerhousing for discharging carrier gas in jet form in the interior volume,for entrainment of medicament from the reservoir portion of the housingin the carrier gas jet, with the nozzle portion comprising a nozzleorifice accommodating carrier gas flow therethrough, wherein the nozzleorifice has an equivalent orifice diameter in the range of from about0.005 inch to about 0.020 inch, preferably from about 0.007 inch toabout 0.018 inch, more preferably from about 0.008 inch to about 0.015inch, and most preferably from about 0.010 inch to about 0.012 inch.Nebulizer vial 50 may suitably comprise a container made to releasiblybut sealably attach to commercially available nebulizer 20 and, incombination with a gravitational or mechanical pump and a large supplyvessel, provide a continuously filled reservoir 72 from which medicantsare aspirated via aspirator tube 66 into nebulizer 20 and aerosolized.Alternatively the nebulizer vial may be of a conventional type,uconnected to any external liquid supply vessel, for delivery of aunitary dose of medicant from the reservoir portion 72 of the nebulizerhousing.

FIG. 3 provides a sectional view of nebulizing device 48, comprisingnebulizer 20 threadably interconnected to nebulizer vial 50. Thefollowing description of nebulizer 20 is provided for a generalunderstanding of the interaction between nebulizer 20 and nebulizer vial50.

Nebulizer 20, as seen in FIG. 3, comprises a housing 262 which comprisesa top nebulizer inflow connecting tube 44', a jet passage member 260,with nozzle orifice 203 in the lower nozzle portion thereof, a baffleassembly 268, and aspirator tube 66. Baffle assembly 268 furthercomprises an aspirator tube connecting orifice 274, a liquid effluentorifice 276, and an impingement baffle 272 in the form of a baffle platepresenting an impingement surface to gas exiting nozzle orifice 203 andliquid entrained in the gas from liquid effluent orifice 276.Pressurized gas which provides the nebulizing high velocity stream fornebulization is provided through top nebulizer inflow connecting tube44'. The high velocity stream is produced by jet passage member 260 inthe direction of impingement baffle 272. As the high velocity streampasses by liquid effluent orifice 276 a resulting below ambient pressureat orifice 276 draws liquid therethrough which is carried by the highvelocity carrier gas stream to impact against the impingement surface ofimpingement baffle 272 to thereby produce a mist.

Housing 262 further comprises a pair of baffles 264 and 266 which lie ininhalation pathway 26 and shield the space where nebulization occurs. Ahollow frustoconical baffle 278 is disposed in the medial space betweeninhalation pathway 26 and the extension of baffles 264 and 266 to limitair flow into nebulizer vial 50 and aid in entraining mist intoinhalation pathway 26. While this description of an illustrativenebulizer embodiment is for a single connecting tube 44', nozzle 260 andassociated parts, the number of inflow connecting tubes, nozzles, andassociated nebulizer parts may vary in the nebulizer as is well known inthe art.

Nebulizer vial 50 is suitably made from synthetic resinous material andpreferably is transparent for easy monitoring by a respiratorytechnician or other patient attendant. The materials of construction ofnebulizer vials are well known in the art. They are usually ofchemically-inert thermoplastic such as polyolefins or polyvinylchlorides. Their selection and fabrication are well within the skill ofthe art.

As seen in FIGS. 2 and 3, nebulizer vial 50 comprises a port 52 and atherethrough inserted feedthrough 74. Also as seen in combination inFIGS. 2 and 3, port 52 may be located at different sites in nebulizervial 50 as required to meet tubing placement and other physical fluiddelivery restrictions. As seen in FIG. 2, tube 54 is engaged aboutfeedthrough 74 to be releasibly but snugly affixed thereat inpressure-sealed relation. Feedthrough 74 comprises a through hole 280,as seen in FIG. 3, through which fluid received under pressure from pump60 flows into nebulizer vial 50. The bottom of nebulizer vial 50comprises an inverted conically shaped part 76. Apex 78 of invertedconically shaped part 76 provides a low point for fluid contained inreservoir 72 where apirating tube 66 end 68 is normally disposed whennebulizer 20 is affixed to nebulizer vial 50. A plurality of legs 80provide a level support when nebulizer vial 50 is disposed on ahorizontal surface to maintain fluid at the bottom of inverted conicallyshaped part 76.

Referring again to FIG. 2, large supply vessel 70, seen to be in theform of a plastic container bag, is disposed on a hook 72', such as anIV bag is hung. Tube 58 provides the fluid pathway to pump 60. Pump 60comprises rate control dial 282 and flow rate display 284 which providefor manual flow rate adjustment. Thereby, the flow rate of pump 60 isset to provide a rate of flow of liquid into nebulizer vial 50 which issubstantially equal to the rate of loss of liquid from the reservoir 72through aerosolization. Such a flow rate for pump 60 is derived from anomogram which comprises the variables of gas flow through flow meter 40and through ventilator 10. A different homogram is generated for eachcombination of nebulizer 20, flow meter 40, and ventilator 10.Derivation of such nomograms is well within the skill of the art. Asdisclosed above, pump 60 is a variable flow controlling pump whichprovides and maintains an accurate and precise flow rate. Pump 60 may bea syringe infusion pump, model number 2001, available from Medfusion, aMedox, Inc. Company, 3450 River Green Court, Duluth, Ga. 30136.

FIG. 4 is a cross-sectional elevation view of a nebulization structure300 which is mountable in the interior volume of a nebulizer housing, asfor example a nebulizer housing of the type illustratively shown anddescribed with respect to FIGS. 1-3 hereof.

Nebulization structure 300 includes a jet passage member 302 having aninlet portion 304 for introduction of carrier gas thereinto, suchcarrier gas being introduced from suitable conduit or flow circuit means(not shown) to effect flow of carrier gas into the inlet portion 304 ofjet passage member 302 in the direction indicated by arrow A in FIG. 4.

Jet passage member 302 further includes a nozzle portion 306, which ispositioned in the interior volume of the nebulizer housing, fordischarging carrier gas in jet form in the interior volume, throughnozzle orifice 308. The nozzle orifice has an equivalent orificediameter in the range of from about 0.05 inch to about 0.020 inch, andpreferably is at least generally circular in cross-sectional shape,transverse to the flow direction indicated by arrow A.

By this arrangement, carrier gas passing through the jet passage member302 flows through the nozzle orifice 308 in the direction indicated byarrow B, with the carrier gas flow rate suitably being on the order offrom about 1.75 to about 3.25 liters per minute.

In this embodiment of FIG. 4, the nebulization structure 300 furthercomprises an expansion chamber 310 in flow-receiving communication withthe nozzle portion 306 of the jet passage member. The expansion 310defines an expansion volume 312 therewithin, and the expansion chamberincludes an orifice 314 through which the carrier gas is flowed in thedirection indicated by arrow C subsequent to entrainment in such carriergas of liquid to be nebulized, which enters the expansion volume 312 inthe direction indicated by arrow D, from extension tube 316 of theexpansion chamber. Expansion tube 316 has a lower open end 318 as shown,and the tube is journaled or otherwise secured in closed flowrelationship to aspiration tube 320 having an interior flow passage 322and a lower open end 324 into which liquid is aspiratingly drawn in thedirection indicated by arrow E.

Secured to the aspiration tube 320, as shown, by means of arm 326 is animpingement member 328 presenting an impingement surface on its upperportion onto which the delivery mixture comprising carrier gas andentrained liquid is impinged, for dispersion in the directions indicatedby arrows F in FIG. 4.

The impingement member 328 may, as shown, feature a convex impingementsurface, whereby dispersion in a wide variety of directions in theinterior volume, is achieved.

In use, the nebulization structure 300 is disposed so that the loweropen end 324 of aspiration tube 320 is disposed in a pool or body ofliquid medicant in the lower reservoir portion of the nebulizer housing.The flow of carrier gas in the direction indicated by sequential arrowsA, B, and C causes a reduced gas pressure in the expansion chamber 312which effects aspiration of liquid through aspiration tube 320 andextension tube 316 to the locus of the expansion chamber 310 interiorvolume 312 in proximity to nozzle orifice 308. By this arrangement, ahighly efficient dispersion of liquid into the gas is achieved, and thedroplet size distribution is extremely favorable for highly efficientnebulization, due to the fineness of the mist liquid particles therebyobtained.

Nozzle orifice 308 may suitably have an equivalent orifice diameter inthe range of from about 0.005 inch to about 0.020 inch, preferably inthe range of from about 0.007 to about 0.018 inch, more preferably fromabout 0.008 inch to about 0.015 inch, and most preferably from about0.010 inch to about 0.012 inch.

At equivalent orifice diameter values below about 0.005 inch, theorifice becomes disporportionately more difficult to reliablymanufacture and fabricate. Above about 0.020 inch, the velocity ofcarrier gas flow achievable by the jet passage member becomes unsuitablylow to accommodate the low gas flow rate nebulization conditions desiredin the practice of the invention. The further preferred, more preferred,and most preferred ranges represent further balances of thesecorresponding considerations associated with the end points of the broadrange of equivalent orifice diameter values.

Similar considerations dictate the range of permissible sizespotentially employable for the expansion chamber orifice 31 4, whichsuitably has an equivalent orifice diameter in the range of from about0.025 inch to about 0.060 inch, and more preferably from about 0.30 inchto about 0.050 inch.

Corresponding operational considerations govern the gas flow rate pastthrough the jet passage member of the nebulizer device. In accordancewith the low flow rate nebulization method of the present invention, thecarrier gas flow rate through the jet passage member is advantageouslyin the range of from about 0.5 to about 3.25 liters per minute, todisperse the medicant into the carrier gas and form a pulmonarilyeffective nebulized medicant in the carrier gas, as a medicant/carriergas mixture. At flow rate values below about 0.5 liters per minute, thevolumetric flow rate of carrier gas tends to become insufficient toachieve good dispersion of the medicant in the flowing gas stream. Atvolumetric flow rate values above about 3.25 liters per minute, thesmall-size orifice dimensions employed in the practice of the inventiontend to produce a back pressure which renders it disporportionately moredifficult to achieve a reliable coupling and seal between the inletportion of the jet passage member and the associated carrier gas flowmeans. Preferably, the volumetric carrier gas flow rate is in the rangeof from about 1.0 to about 3.0 liters per minute, and most preferably isin the range of from about 2.2 to about 2.8 liters per minute, based oncorresponding considerations, as regards the end point values of thepreferred and most preferred ranges, corresponding to the reasons setout above in the respect of the end points of the broad volumetric flowrate range of from about 0.5 to about 3.25 liters per minute. Thenebulizer device and nebulization method of the present invention areusefully employed with any of a wide variety of nebulizable materials,including liquid and solid medicants, liquid medicants beingadvantageously practiced with liquid nebulizer devices in accordancewith the present invention, as illustratively embodied in the deviceshown and described with reference to FIGS. 1-3 hereof, and thenebulization structure alternatively described in connection with FIG. 4hereof; particulate solid, e.g., powdered, medicants may usefully beadministered with powder nebulizer means as more fully shown anddescribed in our prior copending U.S. patent application Ser. No.07/846,784 filed Mar. 4, 1992, the disclosure of which hereby isincorporated herein by reference. An illustrative powder nebulizerpotentially useful in the broad practice of the present invention isillustratively described hereinafter with reference to FIGS. 5 and 6herein.

Illustrative of medicants which may be administered utilizing thenebulization technology of the present invention are materials such aslung surfactants or precursors thereof (precursors being materials orsubstances which are converted in situ in the pulmonary locus tosurfactant material), terbutaline, salbutamol, dexamethasone, chromolynsodium and pentamidine, and bioactive substances encapsulated in apulmonarily degradable encapsulant medium (i.e., a medium in which thebioactive substance is encapsulated and which is degradable in thepulmonary locus to release the bioactive substance). The liquidnebulizer apparatus in accordance with the present invention isparticularly usefully employed for administration of lung surfactants,such as NEOSURF® (Burroughs Wellcome Company, Research Triangle Park,N.C.) and pentamidine, which is usefully employed in the treatment ofpneumocystis infections accompanying HIV infection, and development ofARC and AIDS.

In application to particulate solids nebulization, the present inventioncontemplates a method of forming a solid particle dispersion with theuse of a carrier gas at the low volumetric flow rate values discussedhereinabove, and with a suitably configured nebulizer apparatus,featuring a jet passage member having the dimensional characteristicsdescribed hereinabove.

In the practice of nebulizing particulate solid medicants in thepractice of the present invention, the nebulizer housing includes areservoir portion for the particulate solid medicant, which preferablyis generally conical-shaped or funicular in shape, for containing theparticulate solid to be dispersed. A jet of carrier gas is directeddownwardly through the jet passage member to the lower extremity of suchgenerally conical-shaped or funicular-shaped receptacle to entrainparticles of the particulate solid in the carrier gas, to form a solidsdispersion in the carrier gas which then is discharged from thenebulizer device to suitable breathing circuitry means.

In a preferred particulate solid medicant nebulization system, the gasstream directed at the particulate solid is passed through the nozzleorifice of the jet passage member, then expanded and passed through asecond orifice of the expansion chamber, with an entrainment structurechanneling gas from the receptacle to the jet structure, to increasetotal gas flow and assist in the production of a gas jet flow stream ofdesired velocity and pressure characteristics. The entrainment structuremay comprise a chamber defining a plenum, with an entrainment portcommunicating in gas flow relationship with the interior volume of thehousing, and with an outlet port communicating with the second orificeto cooperatively form a jet structure therewith, as described in theaforementioned prior copending application Ser. No. 07/846,784 now U.S.Pat. No. 5,186,166.

Referring now to the solids nebulization system shown in FIG. 5, apatient 430, undergoing respiratory therapy, is fitted with anendotracheal tube 424. The proximal trunk end 418 of a "Y"-shapedconnector 432 is insertably connected to a distal end 425 ofendotracheal tube 424. Nebulizing device 448 is connected to arm 434 of"Y"-shaped connector 423 via tube 422 which is interposed and connectedbetween exit port 421 of nebulizer device 448 and arm 434 of the"Y"-shaped connector 432 at port 433. A distal end 435 of arm 434 isinsertably connected to a proximal end 414 of gas delivery tube 412. Gasdelivery tube 412 provides the proximal portion of inhalationrespiratory pathway 426 and connects to the output inhalation gas of aventilator 410. Ventilator 410 supplies periodic, breath-sustainingpulses of pressurized gas through tube 412 and through arm 434 of"Y"-shaped connector 432 into endotracheal tube 424 and to patient 430.

The other distal end 436 of "Y"-shaped connector 432 comprises aproximal portion of an exhalation respiratory pathway 428 which furthercomprises tube 416 which returns exhalation flow to ventilator 410. Manydifferent ventilators are known and available in the art. Generally,ventilators which are conventionally used with nebulizers may be usedwith the present invention.

Nebulizer device 448 receives a supply of nebulizing gas from a flowmeter 440 along a fluid pathway 426' which passes through a tube 442interposed and connected between flow meter 440 and a top nebulizerinflow connecting tube 444'. Flow meter 440 receives a pressurized gasfrom a gas source 444 through a connecting tube 442'. Gas pressure fromgas source 444 is sufficient to provide the volumetric flow for whichflow meter 440 is preset. Gas source 444 may comprise pressurized oxygenor other breathable gas from the hospital pressurized oxygen deliverysystem, from a tank of compressed oxygen, a blender, directly fromventilator 410 or from other sources of pressurized gases used inrespiratory therapy. Flow meters are well known and widely used in theart. Such flow meters may comprise macro and vernier adjustable controlsfor very accurate and precise gas flow setting. Although oxygen ispreferred for some selected medicants, gas source 444 may supply oxygenblended with other gases.

Nebulizing device 448 comprises nebulizer upper portion 420 and anebulizer receptacle 450. Nebulizing device 448 nebulizes or aerosolizespowdered medication contained in nebulizer receptacle 450 therebyproducing a mist (particulate solids-in-gas dispersion) which is carriedto patient 430 by influent flow of gas from ventilator 410 throughpathway 426 and by nebulizing gas received from gas source 444.

The nebulizing device 448 comprises nebulizer receptacle 450 which isattached to nebulizer upper portion 420. In a specific embodiment, thetop of the nebulizer receptacle 450 is 1.5 inches in diameter, thebottom is 0.25 inches in diameter, and the nebulizer receptacle 450measures 1.5 inches from top to bottom. As shown in FIG. 6, an end ofnozzle 466 is disposed above the surface of a reservoir 472 in thebottom of the nebulizer receptacle 450.

While specific dimensions and tolerances are ilustratively set forthherein in respect of the preferred embodiments of the invention, it willbe appreciated that the specific size, design, dimensions, andtolerances, may be varied widely within the broad scope of the presentinvention, with the choice of a specific set of such design parametersbeing dependent on the particular end use application contemplated in agiven instance. The present invention may be embodied in the variousembodiments illustrated in our prior co-pending U.S. patent applicationSer. No. 07/729,518, filed Jul. 12, 1991, the disclosure of which ishereby incorporated herein by reference.

FIG. 6 provides a sectional view of nebulizing device 448 of FIG. 5,comprising nebulizer upper portion 420 and nebulizer receptacle 450.

The nebulizer upper portion 420, as seen in FIG. 6, comprises a housing362 which includes a nebulizer inflow connector tube 444', a firstnozzle 360, and a second nozzle 466. Pressurized gas is provided throughnebulizer inflow connecting tube 444'. The high velocity stream of gasfor nebulization is produced by nozzle 360 and nozzle 466. Thepressurized gas is discharged from the second nozzle 466. Thepressurized gas is discharged from the first nozzle 360 into thereceiving volume 465 of the second nozzle 466, thereby undergoingexpansion, following which the gas is discharged into entrainmentassembly 467. As the high velocity gas stream passes through entrainmentassembly 467, a resulting below ambient pressure within entrainmentassembly 467, creates a sufficient pressure differential betweenentrainment port 469 and nebulizer receptacle 450 to draw gas fromnebulizer receptacle 450 through entrainment port 469 and intoentrainment assembly 467 where the entrained gas is added to the highvelocity gas stream being directed toward reservoir 472. The resultinglyaugmented gas stream exits entrainment assembly 467 through outlet port470. The high velocity gas stream thus discharged from jet structure 471engages the powdered medication in the lower portion of nebulizerreceptacle 450, which is of progressively decreasing transversecross-section. As a result, there is achieved a high extent of solidsentrainment in the gas stream, as discharged into inhalation pathway426' via exit 421.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential characteristics thereof. Thepresent embodiments are therefore to be considered in all respects asillustrative and not restrictive, the scope of the invention beingindicated by the appended claims rather than by the foregoingdescription, and all changes which come within the meaning and range ofequivalency of the claims are therefore intended to be embraced therein.

What is claimed is:
 1. A small volume nebulizer device, comprising:(a) ahousing defining a nebulizer receptacle having an interior volumetherewithin, including a reservoir portion for holding medicamenttherein for entrainment into a carrier gas to form a delivery gasmixture comprising nebulized medicament and carrier gas, said nebulizerreceptacle having a size defining said nebulizer device as a smallvolume nebulizer device; (b) a discharge port connected to the housingin flow communication with the interior volume therein, for dischargingthe delivery gas mixture from the housing; (c) means for increasingdelivery of pulmonarily effective aerosol particles at low flow ratesthrough said nebulizer receptacle, comprising:a jet passage memberhaving (i) an inlet means for introduction of carrier gas thereinto and(ii) a nozzle means positioned in the interior volume of the housing fordischarging carrier gas in jet form into the interior volume of saidnebulizer receptacle for entrainment of medicament from the reservoirportion of the housing in the carrier gas jet, said nozzle portioncomprising a nozzle orifice accomodating carrier gas flow therethrough,wherein the nozzle orifice has an equivalent orifice diameter in therange of from about 0.005 inch to about 0.015 inch; an impingementbaffle presenting an impingement surface in alignment with the orificeof the jet passage member; and pressurized carrier gas supply meanscoupled in gas-supplying relationship with the inlet portion of the jetpassage member, for supplying pressurized carrier gas at a flow rate offrom about 0.5 to 2.8 liters per minute.
 2. A device according to claim1, wherein the equivalent orifice diameter is in the range of from 0.008inch to 0.015 inch.
 3. A device according to claim 1, wherein theequivalent orifice diameter is in the range of from 0.010 inch to 0.012inch.
 4. A device according to claim 1, further comprising anebulization structure mounted in the interior volume of the housing,including: an expansion chamber in flow receiving communication with thenozzle portion of the jet passage member, said expansion chamber havingan orifice therein, in alignment with the orifice of the jet passagemember; said impingement baffle presenting an impingement surface inalignment with the orifices of both the jet passage member and theexpansion chamber; and means for aspiratingly delivering liquid from thereservoir portion of the housing when liquid is contained in thereservoir and carrier gas is flowed in sequence through the orifices ofthe jet passage member and the expansion chamber at sufficientvolumetric flow rate.
 5. A device according to claim 4, wherein theorifice in the expansion chamber has an equivalent orifice diameter inthe range of from 0.025 inch to 0.060 inch.
 6. A device according toclaim 4, wherein the orifice in the expansion chamber has an equivalentorifice diameter in the range of from 0.030 inch to 0.050 inch.
 7. Adevice according to claim 1, further comprising a breathing circuitcoupled with the discharge port for receiving delivery gas mixture andconveying same to a patient interconnected with the breathing circuit.8. A device according to claim 1, further comprising means disposed inthe interior volume of the housing for delivering liquid from thereservoir portion of the housing to a discharge locus of the nozzleorifice of the jet passage member, whereby delivered liquid is entrainedin carrier gas flowed through the jet passage member when the reservoirportion contains liquid.
 9. A method of delivering a nebulizedmedicament to a patient, and increasing delivery of pulmonarilyeffective aerosol particles at low flow rates comprising the stepsof:(I) providing a nebulizer apparatus including a breathing circuitcoupled to the patient and including a small volume nebulizer device,wherein the small volume nebulizer device comprises:(a) a housingdefining a nebulizer receptacle having an interior volume therewithin,including a reservoir portion for holding medicament therein forentrainment into a carrier gas to form a delivery gas mixture comprisingnebulized medicament and carrier gas said nebulizer receptacle having asize defining said nebulizer device as a small volume nebulizer device;(b) a discharge port connected to the housing in flow communication withthe interior volume therewith in, for discharging the delivery gasmixture from the housing; (c) means for increasing delivery ofpulmonarily effective aerosol particles at low flow rates through saidnebulizer receptacle, comprising: a jet passage member having (i) aninlet means for introduction of carrier gas thereinto and (ii) a nozzlemeans positioned in the interior volume of the housing for dischargingcarrier gas in jet form into the interior volume of said nebulizerreceptacle, for entrainment of medicament from the reservoir portion ofthe housing in the carrier gas jet, said nozzle portion comprising anozzle orifice comprising a nozzle orifice accomodating carrier gas flowtherethrough, wherein the nozzle orifice has an equivalent orificediameter in the range of from about 0.005 inch to about 0.015 inch; andan impingement baffle presenting an impingement surface in alignmentwith the orifice of the jet passage member; (II) disposing a medicamentin the reservoir portion of the housing; (III) flowing the carrier gasthrough the jet passage member of the jet nebulizer device and nebulizerreceptacle at a flow rate in the range of from about 0.5 to 2.8 litersper minute, to disperse the medicament into the carrier gas and form apulmonarily effective nebulized medicament in the carrier gas, as amedicant/carrier gas mixture; and (IV) passing the medicament/carriergas mixture through the breathing circuit to a pulmonary situs of thepatient.
 10. A method according to claim 9, comprising flowing thecarrier gas flow rate in range of from 1.0 to 2.8 liters per minute. 11.A method according to claim 9, comprising flowing the carrier gas at aflow rate in the range of from 2.2 to 2.8 liters per minute.
 12. Amethod according to claim 9, wherein the medicant comprises a materialselected from the group consisting of lung surfactants or precursorsthereof, terbutaline, salbutamol, dexamethasone, chromolyn sodium,pentamidine, and bioactive substances encapsulated in a pulmonarilydegradeable encapsulant medium.
 13. A method according to claim 9,wherein the medicant comprises a material selected from the groupconsisting of lung surfactant and pentamidine.
 14. A method according toclaim 9, comprising providing the equivalent orifice diameter in therange of from 0.007 inch to 0.018 inch.